The long-term goal of these studies is to identify during the pre-clinical phase of disease those healthy individuals who are at sufficiently high risk for developing Rheumatoid Arthritis (RA) so that a rational primary prevention strategy can be employed. Such a strategy in RA or other autoimmune diseases has been previously thought to be unfeasible. However, extensive experience gained at the University of Colorado Health Sciences Center (UCHSC) in Type 1 or Insulin-Dependent Diabetes Mellitus (IDDM), an autoimmune disease in which disease- related autoimmunity can be detected in the pre-clinical state, has demonstrated that by using several informative strategies one can identify individuals at risk for the development of clinical disease in both the general population and within families. These studies are part of the Diabetes and Autoimmunity Study in the Young (DAISY). With this information, investigators in DAISY are currently employing prevention strategies designed to block the development of clinical signs and symptoms of disease in children with autoimmunity but no significant islet cell dysfunction yet detectable. Using collaborative investigators from the DAISY project, we propose in this funding period to use a very unique population resource of >21,000 HLA typed children and their parents identified during a general population screen in DAISY, as well as adult patients with RA identify by outreach efforts, in order to develop three unique cohorts of individuals at risk for RA. Using these cohorts, we will test the primary hypothesis that pre-clinical evidence of RA- related autoimmunity can be detected in a substantially increased percentage of healthy children and adults who are at increased risk for the development of RA as compared to controls. If this hypothesis is true, our secondary hypothesis will then be that genetic and environmental factors can be identified in these individuals that strongly correlate with pre- clinical RA-related autoimmunity. To test these hypotheses, we propose the following three Specific Aims. Specific Aim #1: Utilize DR4 HLA typing information in the DAISY newborn cohort to identify and characterize DR4-positive parents who are at increased risk for RA in order to determine the age-specific prevalence and incidence of RA- related autoimmunity. Specific Aim #2: Utilize HLA typing information in the DAISY newborn cohort to identify and characterize children for whom the presence of single of compound heterozygote DR0404/0401 alleles substantially increases the risk for RA in order to determine the age-specific prevalence and incidence of RA-related autoimmunity.